3-38622401-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000335.5(SCN5A):c.481G>A(p.Glu161Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,600,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E161Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense, splice_region

Scores

Splicing: ADA: 0.8314

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a transmembrane_region Helical; Name=S2 of repeat I (size 20) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38622401-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant 3-38622401-C-T is Pathogenic according to our data. Variant chr3-38622401-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38622401-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.481G>A	p.Glu161Lys	missense_variant, splice_region_variant	Exon 4 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.481G>A	p.Glu161Lys	missense_variant, splice_region_variant	Exon 4 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.481G>A	p.Glu161Lys	missense_variant, splice_region_variant	Exon 4 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.481G>A	p.Glu161Lys	missense_variant, splice_region_variant	Exon 4 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000415

AC:

AN:

240992

Hom.:

AF XY:

0.00000767

AC XY:

AN XY:

130426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1448478

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720350

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000363

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000586

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 19, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12106943, 20539757, 23414114, 20384651, 29574140, 30847666, 30618807, 33131149, 33221895, 35996667, 17368591, 29473904, 19255801, 15910881, 21357845, 22929165, 34076677, 19251209, 29709244, 30203441, 22581653, 20031634, 20129283, 32268277, 20448214) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 161 of the SCN5A protein (p.Glu161Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Brugada syndrome (PMID: 15910881, 20031634, 21273195). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67927). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15910881, 20539757). For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome 1

Pathogenic:1

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (MIM#608567), whereas gain of function is usually associated with long QT syndrome 3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however sick sinus syndrome is caused by biallelic variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DI-S2 transmembrane region within the ion transporter domain (PMID: 20129283, DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change, p.(Glu161Gln), has been reported in an individual with Brugada syndrome (PMID: 20129283). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified multiple times as pathogenic, and identified in at least eight unrelated individuals with Brugada syndrome, sick sinus syndrome and/or conduction disease (ClinVar, PMID: 30847666, PMID: 15910881, PMID: 20031634, PMID: 20129283, PMID: 32893267). (SP) 0902 - This variant has moderate evidence for segregation with disease, having been shown to segregate in three affected families. However, additional heterozygous individuals with the variant were unaffected, and another individual with Brugada syndrome did not have the variant, suggesting incomplete penetrance (PMID: 15910881, PMID: 20031634). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected A201 cells have been shown to significantly reduce peak sodium current density (PMID: 15910881). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype

Pathogenic:1

Apr 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E161K pathogenic mutation (also known as c.481G>A), located in coding exon 3 of the SCN5A gene, results from a G to A substitution at nucleotide position 481. The glutamic acid at codon 161 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple unrelated individuals with arrythmogenic phenotypes, including Brugada syndrome, sick sinus syndrome, and conduction disease (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Sonoda K et al. Heart Rhythm, 2018 08;15:1179-1188). It has been reported to segregate with disease in two families; however, one genotype-negative individual did exhibit a flecainide-induced Brugada pattern on ECG (Smits JP et al. J. Mol. Cell. Cardiol., 2005 Jun;38:969-81). Several functional studies indicate that E161K results in reduced sodium current in mammalian cells (Smits JP et al. J. Mol. Cell. Cardiol., 2005 Jun;38:969-81; Gui J et al. PLoS ONE, 2010 Jun;5:e10985). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Brugada syndrome

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:12106943;PMID:15910881;PMID:20129283;PMID:20384651;PMID:20448214;PMID:20539757;PMID:19251209). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Uncertain

0.87

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

.;.;.;.;.;D;.;.;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D;D;D;D;D;D;.;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

.;M;.;.;.;M;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D;D;D;D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;.;D;D;.;.;.

Vest4

0.97

MVP

0.97

MPC

1.2

ClinPred

0.99

GERP RS

4.0

Varity_R

0.87

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Benign

0.61

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over